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The effect-site concentration of remifentanil blunting endotracheal intubation responses in elderly patients during anesthesia induction with etomidate: a dose-exploration study

BMC Anesthesiology volume 25, Article number: 70 (2025) Cite this article

Abstract

Purpose

Laryngoscopy and endotracheal intubation are known to increase activity of the sympathetic nervous system, and are usually associated with perioperative hypertension, cardiac arrhythmia, and tachycardia. The aim of this study was to determine the effect-site concentrations of remifentanil to inhibit the tracheal intubation response during etomidate anesthesia in elderly patients.

Methods

American Society of Anesthesiologists physical status I-III patients aged 65 or older and scheduled for general anesthesia for elective surgery were enrolled in the study. Anesthesia induction was applied with etomidate 0.3 mg/kg, rocuronium 0.6 mg/kg, and target controlled infusion of remifentanil under the Minto pharmacokinetic model. Invasive continuous arterial blood pressure monitoring was used throughout the operation. A positive response was defined if the maximal mean arterial pressure (MAP) or heart rate (HR) within 3 min after tracheal intubation was 20% higher than the baseline value. The Dixon sequential method was used for the test, and the initial effect-site concentrations of remifentanil was 6 ng/ml. The EC50 and EC95 for the suppression of endotracheal intubation response by remifentanil were calculated by the probit method.

Results

The EC50 for inhibiting tracheal intubation response by remifentanil in elderly patients was 6.53 ng/ml (95% CI:6.01–7.05 ng/ml) and EC95 was 8.05 ng/ml (95% CI:7.32–8.78 ng/ml) when combined with etomidate anesthesia. The changes of MAP, HR and BIS in positive group were significantly higher than those of negative group (P < 0.05). There were no episodes of hypoxemia, muscular tremor, chest wall rigidity or choking cough in both groups.

Conclusions

Target controlled infusion of remifentanil in combination with etomidate is effective preventing hemodynamic instability in elderly patients during the anesthesia induction and endotracheal intubation.

Clinical trial registration

This article was registered at Chinese Clinical Trial Registry (www.chictr.org.cn registration number: ChiCTR2300076261, date of registration: 28/09/2023).

Peer Review reports

Introduction

The population of geriatric patients undergoing elective surgery and general anesthesia has been gradually increasing worldwide. Elderly patients often have multiple comorbidities including hypertension, atherosclerosis, and coronary artery disease prior to surgery. During general anesthesia, laryngoscopy and endotracheal intubation are known to increase activity of the sympathetic nervous system and usually associated with perioperative hypertension, cardiac arrhythmia, and tachycardia [1]. In addition, older age is an independent risk factor for post-induction hypotension, which increases the risk of severe adverse outcomes, such as myocardial injury, ischemic stroke, or acute kidney injury following surgery [2]. Therefore, preventing hemodynamic fluctuations during general anesthesia and tracheal intubation in elderly patients is of significant clinical value.

Remifentanil is a selective µ-opioid receptor agonist with rapid onset and short duration of action [3,4,5]. The cardiovascular responses to endotracheal intubation can be effectively blunted by remifentanil, due to its ability to inhibit the sympathetic nervous system response. Previous study from our group has reported the application of target-controlled infusion of remifentanil, in combination with etomidate, for anesthesia induction of adult patients [6]. It is suggested that sufentanil, alfentanil, and fentanyl are approximately twice as potent when used in elderly patients, as the brain sensitivity to opioid analgesics increases with age [7]. However, the optimal doses of remifentanil for general anesthesia induction in elderly patients remain unclear. This study was designed to investigate the effect-site concentration of remifentanil required to blunt sympathetic responses undergoing endotracheal intubation during anesthesia with etomidate in patients aged 65 or older.

Methods

Inclusion and exclusion criteria

The Ethics Committee of the Peking University Shenzhen Hospital approved this prospective, double-blind, dose-finding clinical trial (approval number: [2023] No.130) which was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2300076261). After obtaining the written informed consent, ASA physical status I-III patients aged 65 or older and scheduled for general anesthesia for elective surgery were enrolled in the study. Patients with a potentially difficult airway, using opioid analgesics for chronic pain, opioid addiction, having beta-blockers for cardiovascular disease on the day of surgery, taking psychotropic drugs, a history of asthma, hypertension (180/110 mmHg or more), risk of gastric aspiration upon anesthesia induction, body mass index > 35 kg/m2 or adrenocortical insufficiency were excluded from the study.

Study protocol

Before surgery, all patients fasted overnight according to the ASA guideline and received no premedication. An intravenous cannula of 20 gauge was inserted in the pre-anesthesia area, and lactated Ringer’s solution was infused at a dose of 4–6 ml/kg. Standard monitoring with continuous electrocardiography, invasive arterial BP (IBP) monitoring, pulse oxygen saturation (SpO2), and the bispectral index (BIS) were used during the study. Upon arrival in the operating room, patients were preoxygenated with 100% oxygen for three minutes. Remifentanil was intravenously infused at the predetermined Ce under the Minto pharmacokinetic model [8]. 0.15 mg/kg etomidate was given over 15 s at the same time. After the participant lost eyelash reflex, assisted respiration was conducted manually, and rocuronium 0.6 mg/kg was infused over 30 s. 1.5 min after the completion of the rocuronium, a second dose of 0.15 mg/kg etomidate was given over 15 s. Five minutes after the administration of remifentanil, an experienced anesthesiologist performed endotracheal intubation with a unified visual laryngoscope (E. An IIL, Tianjin Medan Medical corporation, China) General anesthesia was maintained using 1.5% sevoflurane with 50% oxygen, end-tidal carbon dioxide concentrations were maintained at 35–45mmHg using mechanical ventilation. The effect-site concentration of remifentanil was then adjusted to 2–4 ng/ml. The timing of different events and the overall study design are presented in Fig. 1.

Fig. 1
figure 1

The research protocol. TCI, target-controlled infusion

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Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean artery pressure (MAP), heart rate (HR), SpO2, and BIS were recorded continually from pre- anesthesia induction until 3 min after tracheal intubation. Values of some specific time points are used to analyze. In this study, T1 was defined as 3 min before induction; T2 was defined as baseline (the mean of measurements taken 2 min and 1 min before intubation); T3 was defined as the immediate moment of intubation; T4 was defined as the maximum value after intubation, T5, T6, T7 were defined as 1 min, 2 min, and 3 min after intubation, respectively. The absolute value of changes of MAP, HR, and BIS during intubation (ΔMAP, ΔHR, and ΔBIS) were defined as the difference between the baseline and the maximal value within the first 3 min following intubation. The variation amplitude of MAP, HR, and BIS (ΔMAP%, ΔHR%, and ΔBIS%) were defined as ΔMAP, ΔHR, and ΔBIS divided by the baseline.

A modified Dixon’s up-and-down method was used to calculate the concentration of remifentanil [9, 10]. Based on previous studies, the effect-site concentration of remifentanil used in the first patient was 6 ng/ml [6, 11]. If the cardiovascular response during endotracheal intubation was positive (defined as MAPmax or HRmax is 20% higher than the baseline value), the concentration of remifentanil in the next patient would increase by 1ng/ml. Conversely, if the intubation response was negative, the concentration of remifentanil would decrease by 1ng/ml. According to the study design, following the first three “negative-positive” crossovers, the step change of dose was reduced to 0.5 ng/ml, and this process was repeated until seven crossover points had been obtained.

During the study period, intravenous ephedrine (0. 1 mg/kg) was administered if the MAP was below 65 mmHg or SBP fell more than 30% of the baseline value [12,13,14]; Intravenous atropine (0.5 mg) was given if the heart rate was less than 40 bpm [15]; Metoprolol was injected (1.5 mg) at HR > 120 bpm; Urapidil (5–25 mg) was given with SBP ≥ 180 mmHg. If MAP and or HR fluctuated to a level that required the administration of a vasoactive drug, the patient was withdrawn from the study, and the same concentration of remifentanil was repeated in the following case.

The patients and the anesthesiologist for endotracheal intubation were not aware of the dose of remifentanil. An assistant anesthesiologist was responsible for administering remifentanil and the induction procedure, this anesthetist was not involved in determining the remifentanil concentration for the intubation. Another anesthetist recording various data, and calculating the dose of remifentanil according to the previous patient’s response.

Outcome measures

The primary outcomes were effective concentration of remifentanil blunting cardiovascular responses of intubation during etomidate anesthesia in 50% (EC50) and 95% (EC95) of the study population. Following EC50 calculation, the data were further analyzed for secondary outcomes to compare those who were positive and negative for tracheal intubation responses. The secondary outcomes including: (1) The changes of the hemodynamic indices (ΔMAP and ΔHR) and indices derived from electroencephalogram (ΔBIS) during endotracheal intubation; (2) adverse events (excessive hemodynamic change, hypoxemia, muscle tremor, symptoms of chest wall rigidity, and choking cough) related to remifentanil combined with etomidate anesthesia.

Statistical analysis

The calculation of sample size is based on Kim’s research and our pilot study [6, 16]. We hypothesized that the EC50 of remifentanil for endotracheal intubation in elderly patients were 6.0 ng/ml. Calculating the sample size was based on a pretest. Assuming the standard deviation (SD) was 0.71 ng/ml and the standard error of mean (SEM) was 0.23 ng/ml. Following Dixon and Massey’s suggestion, the sample size needed to estimate EC50 was derived by N = 2*(SD/SEM)2, a minimum of 23 samples would be required for this study, taking into account a 15% sample loss rate [17]. The statistical analysis was performed using SPSS version 26. 0 software (IBM, Armonk, NY, USA). We calculated the EC50 and EC95 using a probit analysis. Statistical results are presented as point estimates (95% CI). To assess goodness-of-fit, Pearson’s chi-square test was used (P value > 0.05 indicates good fit). For continuous variables, data are expressed as the mean ± standard deviation. For categorical variables, data are expressed as the number (percentage) of patients. A Shapiro-Wilk test was used to check for the normal distribution of continuous variables. The t-test was used to compare parametric data. Categorical variables were analyzed by the Chi‑square test or Fisher’s exact test. A P value < 0.05 (two-tailed) was defined as statistically significant.

Results

Twenty-nine patients were screened for eligibility and all of them were recruited in the study. Three patients were excluded from the study because of the not well-controlled hypertension (OR admission SBP > 180mmHg). Figure 2 illustrates the recruitment pathway. Table 1 shows the demographic data and surgical characteristics. According to the pre-defined intubation response, patients were divided into positive and negative groups. The age, sex, height, weight, BMI, and ASA physical status were comparable between the Positive and Negative groups. There was no significant difference in comorbidities except coronary heart disease.

Fig. 2
figure 2

Consort flow diagram of this study

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Table 1 Demographic and clinical characteristics of patients
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Figure 3 illustrates the dose-response curve of the remifentanil concentration and the probability that a negative intubation response would occur. The EC50 and EC95 of remifentanil blunting cardiovascular responses to intubation during etomidate anesthesia were 6.53 ng/ml (95%CI: 6.01–7.05 ng/ml) and 8.05 ng/ml (95%CI: 7.32–8.78 ng/ml). Pearson’s Chi‑squared goodness‑of‑fit (χ2 = 1.376, P = 0.711). Figure 4 shows individual responses to endotracheal intubation according to the up-and-down sequence.

Fig. 3
figure 3

The effect-site concentration and response curve from the probit analysis. The EC50 for tracheal intubation response inhibition by remifentanil in elderly patients was 6. 53 ng/ml and EC95 was 8. 05 ng/ml, respectively

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Fig. 4
figure 4

Individual responses to endotracheal intubation according to the up-and-down method. The initial dose of remifentanil was 6 ng/ml. A higher effect-site concentration of remifentanil was given to the next patient when a patient showed positive hemodynamic response (open circle). A lower effect-site concentration of remifentanil was given to the next patient when a patient showed negative hemodynamic response (solid circle)

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Changes in HR, MAP, SBP and BIS during the endotracheal intubation are shown in Fig. 5. Compared with baseline values, the values of HR、MAP、SBP and BIS were significantly decreased before intubation in both groups (P < 0.05). ΔMAP, ΔHR and ΔBIS during induction of two groups are presented in Table 2. The changes of ΔMAP、ΔHR、ΔBIS of positive group were significantly higher than that of negative group (P < 0.05). Of note, the MAP increased by 13.63% and HR increased by 34.41% from baseline to the maximal values after intubation in the positive group. There were no differences between groups in BIS at any time point.

Fig. 5
figure 5

Changes in HR, MAP, SBP and BIS during the endotracheal intubation. Data are presented as mean, CI confidence interval. T: Time points. T0: enter the operating room; T1: before induction; T2: baseline; T3: immediate of intubation; T4: the maximum value after intubation; T5: 1 min after intubation; T6:2 min after intubation; T7: 3 min after intubation. Time points do not represent the sequence of events. *P < 0. 05 when compared between the groups

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Table 2 The changes of the hemodynamic indices (△MAP and △HR) and indices derived from electroencephalogram (△BIS) during endotracheal intubation
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One patient was withdrawn from the study as a result of HR>120 bpm requiring administration of metoprolol. There were no episodes of hypoxemia, muscular tremor, chest wall rigidity, choking cough in both groups (Table 3).

Table 3 Incidence of adverse events
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Discussion

Using a modified Dixon’s up-and-down method, our study demonstrated that the EC50 and EC95 of remifentanil required for blunting hemodynamic responses to endotracheal intubation in elderly patients during etomidate anesthesia with rocuronium were 6. 53 ng/ml and 8. 05 ng/ml, respectively.

Endotracheal intubation is usually associated with perioperative hemodynamic fluctuations, such as cardiac arrhythmias and hypertension. These hemodynamic changes are caused by increased activity of the sympathetic nervous system [1]. In elderly patients, extreme hemodynamic changes are associated with higher risk of perioperative complications. There has been evidence that lidocaine, adrenergic blockers, calcium channel blockers, vasodilators, and opioids can attenuate intubation responses [18,19,20]. They also have unexpected side effects like hypotension, bradycardia, and muscle rigidity [19, 21].

Remifentanil is a selective µ-opioid receptor agonist that has rapid onset, short latency and short blood-effect-site equilibration time, and is more suitable for the management of anesthesia in the elderly. Several studies have shown that the use of remifentanil in combination with propofol may provide adequate conditions for laryngoscopy and tracheal intubation with or without muscle relaxants [5, 22]. Habib et al. reported that administration of remifentanil 0.5 ug/kg followed by continuous infusion at 0.1 µg/kg/min in elderly patients was effective in suppressing hemodynamic responses during laryngoscopy and tracheal intubation [23]. Casati et al. reported that continuous infusion of 0.1 ug/kg/min after remifentanil 1 µg/kg was effective in suppressing cardiovascular changes induced by tracheal intubation [24]. Nakada J et al. compared the use of remifentanil 0.2 µg/kg/min and 0.7 µg/kg/min, and found that both dose suppressed intubation responses, but with the dose of 0.7 µg/kg/min, the incidence of chest wall rigidity, dyspnea, and respiratory depression were 46% and 9.1% [25].

To deliver a more stable analgesic concentration of remifentanil, we used TCI as a continuous infusion method by integrating the infusion time, the pharmacokinetic properties of remifentanil, and the patient’s characteristics (gender, age, height, and weight), to improve hemodynamic stability [26, 27]. Our study demonstrated that the EC50 of remifentanil required for blunting hemodynamic responses to endotracheal intubation was 6.53 ng/ml. This concentration is about 1.2 ng/ml lower than that in adult patients (7.731 ng/ml) [6]. Several studies have reported that half-effective effector compartment concentration (Ce50) for remifentanil to suppress the sympathetic response to tracheal intubation in elderly patients is from 3 to 5 ng/ml when remifentanil was combined with propofol, remimazolam, or thiopental et al. [28,29,30]. Effect-site concentrations of remifentanil from these experiments are lower than our study, maybe due to the sympathetic inhibition effect of propofol and remimazolam [29, 31].

A successful anesthesia induction is not only consisted of blunting intubation responses, but also avoiding anesthesia induced hypotension, both of which are key goals of anesthesia management for elderly patients. There were no complications related to the high concentration of remifentanil, such as chest wall rigidity, bradycardia, or hypotension. This is likely because etomidate was used as the induction agent, which does not reduce myocardial contractility and systemic vascular resistance. Various studies have reported improved hemodynamic stability of etomidate compared with propofol [32,33,34]. Remifentanil in combination with propofol for anesthesia induction frequently triggers hypotension before and after intubation [4]. There were no episodes of muscular tremor, chest wall rigidity and choking cough in our study. Remifentanil is also effective in preventing myoclonus that occurs during etomidate induction [35, 36]. Administering rocuronium in the early stages of anesthesia induction is also help to alleviate remifentanil induced muscle rigidity or coughing.

In the current study, an invasive artery blood pressure was continuously monitored, which is more accurate than non-invasive blood pressure measurement at a defined time interval. We found that the peak value of MAP and HR usually occurred between 40 to 60 s after intubation. None of the patients experienced hypotension during our study sampling period. The incidence of hypotension is as high as 47% in previously reported fentanyl complexed etomidate anesthesia induction regimen [37]. In another study, using 3 µg/kg fentanyl in elderly patients, Splinter and Cervenko reported post-induction hypotension in 33% of patients [38]. Although the relative potency of fentanyl to remifentanil is 1:1, the long duration of action of fentanyl of up to 30–60 minutes increases the incidence of hypotension after induction, the incidence of hypotension in the fentanyl study may also have stemmed from the use of propofol. Therefore, we considered etomidate and remifentanil as a better combination for anesthesia induction for elderly patients.

The changes in amplitude of MAP and HR in positive group were significantly higher than that of negative group in the current study, which is in contrast to the only increase of heart rate in adult patients in our previous study [6]. This suggests that blood pressure fluctuates more easily in elder patients and requires more delicate anesthesia management.

In addition to the anesthesia induction drugs and dosing, the timing and order of the drugs are also important factors that may affect hemodynamic stability. Previous studies have demonstrated that remifentanil should be infused for at least 4 minutes before intubation to minimize the prediction error of the steady-state drug concentration at the time of observation [39, 40]. We performed intubation 5 minutes after the initiation of remifentanil TCI so as to allow equilibration between blood and effect-site. Etomidate was administered at two doses of 0.15 mg/kg, with a time interval of 3 minutes. Furthermore, simultaneous injection of remifentanil and etomidate allows early initiation of manually assisted ventilation to avoid hypo-ventilation-associated hypoxia and hypercapnia.

This study has some limitations. First, patients taking beta-blockers on the day of surgery were not considered as an inclusion criteria, because oral premedication with beta-blockers could attenuate the hypertensive response to tracheal intubation [41]. Further study could investigate patients with more complicated conditions including preoperative taking various medications. Second, although our study protocol does not restrict the upper age limit, the oldest patient recruited in this study was 78 years old. Thus, whether our finding is applicable to patients older than 80 years will need to be further validated.

Conclusion

In summary, the use of remifentanil in combination with etomidate for the induction of anesthesia in the elderly is able to avoid hemodynamic instability. The EC50, EC95 of tracheal intubation response inhibition by remifentanil target-controlled infusion in elderly patients were 6.53ng/ml and 8.05ng/ml, respectively, when combined with etomidate at 0.3 mg/kg. Our study provides validity and safety for future application of remifentanil and etomidate in the induction of anesthesia in an elderly population who are medically compromised.

Data availability

The datasets of this study are not publicly available because relevant policies of the Ethics Committee, but they are available from the corresponding author on reasonable request.

Abbreviations

EC50 :

Median effective concentration

EC95 :

95% effective concentration

ASA:

American Society of Anesthesiologists

BMI:

Body mass index

TCI:

Target-controlled infusion

MAP:

Mean arterial pressure

HR:

Heart rate

BIS:

Bispectral index

EEG:

Electroencephalogram

CI:

Confidence interval

ECG:

Electrocardiograms

SpO2:

Pulse oximetry

IBP:

Invasive arterial blood pressure

PetCO2 :

End-tidal carbon dioxide

SBP:

Systolic blood pressure

DBP:

Diastolic blood pressure

SD:

Standard deviation

SEM:

Standard error of the mean

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Acknowledgements

The authors wish to the anesthesiologists in the Institute of the department of anesthesiology, Peking University Shenzhen Hospital, for their support of collaboration.

Funding

This work was supported by Shenzhen Medical Research Fund (Grant No. C2301010).

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Authors and Affiliations

  1. Department of Anesthesiology, Peking University Shenzhen Hospital, Shenzhen, Guangdong Province, China

    Zhimin Hao, Zhencong Jiang, Jiexiong Li & Tao Luo

  2. Shantou University Medical College, Shantou, China

    Zhimin Hao

  3. Department of Anesthesiology, Southern University of Science and Technology Hospital, Shenzhen, Guangdong Province, China

    Zhimin Hao

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  1. Zhimin Hao
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Contributions

TaoLuo, the corresponding author of this article in charge of the project administration, was responsible for the conceptualization and supervision of the study and writing – review and editing the manuscript. Zhimin Hao was the first author of this article, responsible for the experiment, software and writing the original draft of the manuscript. Zhencong Jiang and Jiexiong Li were involved in the data curation, methodology, formal analysis of the study.

Corresponding author

Correspondence to Tao Luo.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Peking University Shenzhen Hospital (approval number: [2023] No.130) and was registered at the Chinese Clinical Trial Registry (registration number: ChiCTR2300076261) on 28/09/2023. Patients were consented by an informed consent process that was reviewed by the Ethics Committee of the Peking University Shenzhen Hospital and certify that the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki.

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Not applicable.

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The authors declare no competing interests.

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Hao, Z., Jiang, Z., Li, J. et al. The effect-site concentration of remifentanil blunting endotracheal intubation responses in elderly patients during anesthesia induction with etomidate: a dose-exploration study. BMC Anesthesiol 25, 70 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12871-024-02844-8

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12871-024-02844-8

Keywords

BMC Anesthesiology

ISSN: 1471-2253

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